IL-17A is an inflammatory cytokine initially identified as a transcript selectively expressed by activated T cells. IL-17RA is a ubiquitously expressed and shown to bind IL-17A with an affinity of approximately 0.5 nM (Yao et al., 1995, Immunity 3:811-821). Five additional IL-17-like ligands (IL-17β-IL-17F) and four additional IL-17RA-like receptors (IL-17RB-IL-17RE) have been identified (Kolls and Linden, 2004, Immunity 21:467-476).
IL-17RC has been shown to bind IL-17A and IL-17F. The observations that IL-17RA deficiency and IL-17RA antibody neutralization ablate both IL-17A and IL-17F function suggest that IL-17RC cannot deliver an IL-17A or IL-17F signal in the absence of IL-17RA (Toy et al., 2006, J. Immunol. 177:36-39; McAllister et al., 2005, J. Immunol. 175:404-412). Additionally, forced expression of IL-17RC in IL-17RA deficient cells does not restore IL-17A or IL-17F function (Toy et al., 2006, J. Immunol. 177:36-39).
IL-17A and IL-17F are predominantly expressed by activated CD4+ memory T cells (Kolls and Linden, 2004, supra). It has been proposed that an IL-17A-producing pathogenic CD4+ T cell subset, ThIL-17, is expanded in the presence of IL-23 (Langrish et al., 2005, J. Exp. Med. 201:233-240). Additionally, both IL-15 and the TNF superfamily member OX40L have been shown to induce the expression of IL-17A (Nakae et al., 2003b, Proc. Natl. Acad. Sci. U.S.A. 100:5986-5990; Ziolkowska et al., 2000, J. Immunol. 164:2832-2838). IL-6 and TGF-beta also induce the expression of IL-17A.
IL-17A and IL-17F bind and activate IL-17RA. IL-17RA has been shown to be important in regulating immune responses. Activation of the IL-17RA leads to production of cytokines, chemokines, growth factors, and other proteins that contribute to the symptoms and/or pathology of numerous diseases. IL-17A is an inflammatory cytokine that induces the production of cytokines and other mediators leading to diseases and physiological effects such as inflammation, cartilage degradation, and bone resorption. IL-17A also plays a role in a number of inflammatory conditions including arthritis (rheumatoid arthritis), psoriasis, inflammatory bowel disease, multiple sclerosis, and asthma. (Li et al., 2004, Huazhong Univ. Sci. Technolog. Med. Sci. 24:294-296; Fujino et al., 2003, Gut. 52:65-70; Kauffman et al., 2004, J. Invest. Dermatol. 123:1037-1044; Mannon et al., 2004, N. Engl. J. Med. 351:2069-2079; Matusevicius et al., 1999, Mult Scler 5, 101-104; Linden et al., Eur Respir J. 2000 May; 15(5):973-7; Molet et al., 2001, J. Allergy Clin. Immunol. 108:430-438). Recent studies have suggested that IL-17F plays a role in the induction of inflammatory responses (Oda et al., 2006, American J. Resp. Crit. Care Medicine, Jan. 15, 2006; Numasaki et al., 2004, Immunol Lett. 95:97-104).
Aspects of the invention provide for the treatment of disease using antibodies that specifically bind IL-17RA and inhibit IL-17RA activation mediated by IL-17 family members